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Allergic rhinitis (AR) is commonly associated with olfactory loss, although the mechanism is not well studied. This study was designed to determine the effect of mometasone furoate (MF) on olfactory loss in seasonal AR (SAR) and study its effect on inflammation in the olfactory region. We performed a randomized, double-blind, placebo-controlled, parallel clinical trial in 17 patients with SAR who had symptoms of impaired olfaction. Subjects received MF or placebo for 2 weeks during their allergy season. Before and after treatment, we measured nasal peak inspiratory flow (NPIF), chemosensory quality of life, and objective olfactory function (the University of Pennsylvania Smell Identification Test). Additionally, nasal cytology samples were obtained from each visit, and a unilateral endoscopic biopsy specimen of the olfactory epithelium was obtained at the end of the study and scored for inflammation. Treatment with MF was associated with improved nasal symptoms (p < 0.015), NPIF (p < 0.04), reduced nasal inflammation (p < 0.05), and chemosensory-specific quality of life (p < 0.03). Histological analysis of the olfactory region reveals fewer eosinophils in the MF group when compared with placebo (p < 0.012). We found no improvement in objective olfactory function (p > 0.05). The use of MF in SAR is associated with reduced eosinophilic inflammation in the olfactory region and improved symptoms of AR. The presence of eosinophils in the olfactory area in SAR may indicate a direct, deleterious effect of inflammation on olfactory epithelium in this disease. In this study we show that inflammation in SAR can affect the olfactory cleft, implicating a direct role for allergic inflammation in smell loss. Treatment with intranasal steroids is associated with decreased inflammation in the olfactory region in humans. This treatment is also associated with improved olfactory quality of life.

Background It is widely assumed that apoptosis of eosinophils is a central component of resolution of allergic airway disease. However, this has not been demonstrated in human allergic airways in vivo. Based on animal in vivo observations we hypothesised that steroid-induced resolution of human airway eosinophilic inflammation involves inhibition of CCL5 (RANTES), a CC-chemokine regulating eosinophil and lymphocyte traffic, and elimination of eosinophils without evident occurrence of apoptotic eosinophils in the diseased tissue. Objective To determine mucosal eosinophilia, apoptotic eosinophils, general cell apoptosis and cell proliferation, and expression of CCL5 and CCL11 (eotaxin) in human allergic airway tissues in vivo at resolution of established symptomatic eosinophilic inflammation. Methods Twenty-one patients with intermittent (birch and/or grass) allergic rhinitis received daily nasal allergen challenges for two seven days' periods separated by more than two weeks washout. Five days into these \"artificial pollen seasons\", nasal treatment with budesonide was instituted and continued for six days in a double blinded, randomized, placebo-controlled, and crossover design. This report is a parallel group comparison of nasal biopsy histochemistry data obtained on the final day of the second treatment period. Results Treatments were instituted when clinical rhinitis symptoms had been established. Compared to placebo, budesonide reduced tissue eosinophilia, and subepithelial more than epithelial eosinophilia. Steroid treatment also attenuated tissue expression of CCL5, but CCL11 was not reduced. General tissue cell apoptosis and epithelial cell proliferation were reduced by budesonide. However, apoptotic eosinophils were not detected in any biopsies, irrespective of treatment. Conclusions Inhibition of CCL5-dependent recruitment of cells to diseased airway tissue, and reduced cell proliferation, reduced general cell apoptosis, but not increased eosinophil apoptosis, are involved in early phase steroid-induced resolution of human allergic rhinitis.

ABSTRACT Background: This study was designed to evaluate the efficacy and safety of fluticasone furoate nasal spray (FFNS), a novel enhanced-affinity intranasal corticosteroid, in Japanese patients with perennial allergic rhinitis (PAR), and to determine the optimal dose. Methods: In this phase II, multicenter, double-blind, randomized, placebo-controlled, parallel-group, dose-ranging study, 240 patients (aged ≥ 16 years) received once-daily (od) treatment for 2 weeks with either FFNS 110 μg (n = 80), 220 μg (n = 81) or placebo (n = 79). Patients evaluated 3 nasal symptoms using a 4-point scale. Efficacy was assessed as the mean change from baseline in total nasal symptom score (TNSS). Results: Treatment with FFNS resulted in a significantly greater decrease over the treatment period in the mean 3TNSS (sneezing, rhinorrhea, and nasal congestion; p < 0.001 each dose vs. placebo), compared with placebo. More patients receiving FFNS had a markedly or moderately improved impression of treatment than placebo recipients (48% and 49% for FFNS 110 μg and 220 μg, respectively, vs. 18% for placebo; p < 0.001). Nasal rhinoscopy findings revealed significant improvements in mucosal swelling of the inferior turbinate (110 μg: p = 0.004; 220 μg: p = 0.011) and amount of watery rhinorrhea (110 μg: p = 0.003; 220 μg: p < 0.001), compared with placebo. Both doses of FFNS were well tolerated. Conclusions: Both FFNS 110 µg and 220 µg od were effective in alleviating nasal symptoms in Japanese patients with PAR over the 2-week duration of this study. FFNS 110 µg od was selected as the optimal dose for further evaluation in phase III clinical trials.

Risk factors that contribute to inter-individual differences in the age-of-onset of allergic diseases are poorly understood. The aim of this study was to identify genetic risk variants associated with the age at which symptoms of allergic disease first develop, considering information from asthma, hay fever and eczema. Self-reported age-of-onset information was available for 117,130 genotyped individuals of European ancestry from the UK Biobank study. For each individual, we identified the earliest age at which asthma, hay fever and/or eczema was first diagnosed and performed a genome-wide association study (GWAS) of this combined age-of-onset phenotype. We identified 50 variants with a significant independent association (P<3x10-8) with age-of-onset. Forty-five variants had comparable effects on the onset of the three individual diseases and 38 were also associated with allergic disease case-control status in an independent study (n = 222,484). We observed a strong negative genetic correlation between age-of-onset and case-control status of allergic disease (rg = -0.63, P = 4.5x10-61), indicating that cases with early disease onset have a greater burden of allergy risk alleles than those with late disease onset. Subsequently, a multivariate GWAS of age-of-onset and case-control status identified a further 26 associations that were missed by the univariate analyses of age-of-onset or case-control status only. Collectively, of the 76 variants identified, 18 represent novel associations for allergic disease. We identified 81 likely target genes of the 76 associated variants based on information from expression quantitative trait loci (eQTL) and non-synonymous variants, of which we highlight ADAM15, FOSL2, TRIM8, BMPR2, CD200R1, PRKCQ, NOD2, SMAD4, ABCA7 and UBE2L3. Our results support the notion that early and late onset allergic disease have partly distinct genetic architectures, potentially explaining known differences in pathophysiology between individuals.

Altered DNA methylation patterns in CD4(+) T-cells indicate the importance of epigenetic mechanisms in inflammatory diseases. However, the identification of these alterations is complicated by the heterogeneity of most inflammatory diseases. Seasonal allergic rhinitis (SAR) is an optimal disease model for the study of DNA methylation because of its well-defined phenotype and etiology. We generated genome-wide DNA methylation (N(patients) = 8, N(controls) = 8) and gene expression (N(patients) = 9, Ncontrols = 10) profiles of CD4(+) T-cells from SAR patients and healthy controls using Illumina's HumanMethylation450 and HT-12 microarrays, respectively. DNA methylation profiles clearly and robustly distinguished SAR patients from controls, during and outside the pollen season. In agreement with previously published studies, gene expression profiles of the same samples failed to separate patients and controls. Separation by methylation (N(patients) = 12, N(controls) = 12), but not by gene expression (N(patients) = 21, N(controls) = 21) was also observed in an in vitro model system in which purified PBMCs from patients and healthy controls were challenged with allergen. We observed changes in the proportions of memory T-cell populations between patients (N(patients) = 35) and controls (N(controls) = 12), which could explain the observed difference in DNA methylation. Our data highlight the potential of epigenomics in the stratification of immune disease and represents the first successful molecular classification of SAR using CD4(+) T cells.

Allergic rhinitis (AR) is a chronic disease affecting a large amount of the population. To optimize treatment and disease management, it is crucial to detect patients suffering from severe forms. Several tools have been used to classify patients according to severity: standardized questionnaires, visual analogue scales (VAS) and cluster analysis. The aim of this study was to evaluate the best method to stratify patients suffering from seasonal AR and to propose cut-offs to identify severe forms of the disease. In a multicenter French study (PollinAir), patients suffering from seasonal AR were assessed by a physician that completed a 17 items questionnaire and answered a self-assessment VAS. Five methods were evaluated to stratify patients according to AR severity: k-means clustering, agglomerative hierarchical clustering, Allergic Rhinitis Physician Score (ARPhyS), total symptoms score (TSS-17), and VAS. Fisher linear, quadratic discriminant analysis, non-parametric kernel density estimation methods were used to evaluate miss-classification of the patients and cross-validation was used to assess the validity of each scale. 28,109 patients were categorized into \"mild\", \"moderate\", and \"severe\", through the 5 different methods. The best discrimination was offered by the ARPhyS scale. With the ARPhyS scale, cut-offs at a score of 8-9 for mild to moderate and of 11-12 for moderate to severe symptoms were found. Score reliability was also acceptable (Cronbach's α coefficient: 0.626) for the ARPhyS scale, and excellent for the TSS-17 (0.864). The ARPhyS scale seems the best method to target patients with severe seasonal AR. In the present study, we highlighted optimal discrimination cut-offs. This tool could be implemented in daily practice to identify severe patients that need a specialized intervention.

Recently, it is claimed that the usage of the intranasal glucocorticosteroids alone, instead of H1-antihistamines + intranasal glucocorticosteroids, reduces the complaints in moderate-to-severe seasonal allergic rhinitis (SAR). This study aims to evaluate the efficacy of the intranasal glucocorticosteroids alone during the pollen season by using objective and subjective parameters. Twenty-four patients (mean age, 12.17 ± 2.26 years) with SAR sensitive to pollen are included in this study. The patients were divided into two groups randomly. Twelve patients in group I were given H1-antihistamine (loratadine) + intranasal glucocorticosteroid (mometasone furoate), and 12 patients in group II were given only intranasal glucocorticosteroid (mometasone furoate) for 12 weeks. To evaluate the results, subjective parameters (daytime nasal symptoms score, daytime eye symptoms score, and nighttime symptoms score) and objective parameters (nasal smear, nasal peak inspiratory flow [NPIF], and nasal biopsy) are used. With regard to the baseline data, it was observed that both groups had a significant decrease in total symptom score (p < 0.01), a significant increase in NPIF values (p < 0.01), and a significant decrease in the number of eosinophils in both nasal smear and biopsy (p < 0.01) after treatment. Comparing groups I and II in terms of treatment success, the improvement in daytime nasal symptoms score (p < 0.01 versus p < 0.01), daytime eye symptoms score (p < 0.01 versus p < 0.01), and total symptom score (p < 0. versus p < 0.01) was not different. However, there was a significant improvement in nighttime symptoms score between groups I and II (p < 0.01 versus p > 0.05). Furthermore, NPIF and nasal biopsy findings did not differ between groups (p > 0.05). The usage of H1-antihistamine + intranasal glucocorticosteroid has no superiority over the administration of intranasal glucocorticosteroid alone for treatment of SAR in pollen season. However, this finding needs to be confirmed in larger series studies.

Gluconacetobacter hansenii (G. hansenii) is an acetic acid bacterium of vinegar production. Its anti-allergic effect on mice upon oral administration was examined. The amount of LPS was measured by the Limulus reaction. Mice were sensitized by peritoneal and intranasal administration of cedar pollen and alum followed by oral administration of 30 or 150 mg/kg of heated G. hansenii cells. Pollen was administered intranasally to evaluate nasal symptoms, and at 8 weeks, IgE and IL-10 levels in blood were measured by ELISA. The amount of LPS in dried bacterial cells was 10.4±3.3 mg/g. In the cedar pollinosis model of mice, a significant reduction was observed in nose scratching of both groups administered with the bacterial cells (30, 150 mg/kg). G. hansenii contains LPS, and its oral administration showed an anti-allergic effect by a significant mitigation of the symptoms in a pollen allergy mouse model.

In seed plants, pollen grains carry the male gametes to female structures. They are frequent in the ambient air, and cause airway inflammation in one out of four persons in the population. This was traditionally attributed to soluble glycoproteins, leaking into the nasal mucosa or the conjunctiva, and able to bind antibodies. It is now more and more recognized that also other immunomodulating compounds are present. Lipids bind to Toll-like and PPARγ receptors belonging to antigen-presenting cells in the mammal immune system, activate invariant Natural Killer T-cells, and are able to induce a Type 2 reaction in effector cells. They may also mimic lipid mediators from mammal mast cells. Pollen grains have a rich lipodome of their own. Among the lipids that have been associated with an atopic reaction are saturated and unsaturated fatty acids, glycophospholipids, sphingolipids, sterols, and oxylipids, as well as lipopolysaccharides from the microbiome on the pollen surface. Lipids can be ligands to allergenic proteins.

Current allergen-specific immunotherapy (AIT) for pollinosis requires long-term treatment with potentially severe side effects. Therefore, development of an AIT that is safe and more convenient with a shorter regimen is needed. This prospective, double-blind, placebo-controlled trial randomized 55 participants with Japanese cedar pollinosis (JCP) to active or placebo groups to test the safety and efficacy of short-term oral immunotherapy (OIT) with Cry j 1-galactomannan conjugate for JCP. Mean symptom-medication score as the primary outcome in the active group improved 27.8% relative to the placebo group during the entire pollen season. As the secondary outcomes, mean medication score in active group improved significantly, by 56.2%, compared with placebo during the entire pollen season. Mean total symptom score was similar between active and placebo groups during the entire pollen season. There were no severe treatment-emergent adverse events in the active and placebo groups. Therefore short-term OIT with Cry j 1-galactomannan conjugate is safe, and effective for reducing the amount of medication use for JCP.